Targeting white matter microgliosis using minocycline in a co‐morbid preclinical rat model of Alzheimer’s disease and stroke
Bibliographic record
Abstract
Current literature indicates a potential synergistic interaction between stroke and Alzheimer’s disease (AD). White matter (WM) inflammation, which is commonly triggered by cerebrovascular disease and AD, disrupts the normal function of white matter; and can trigger and exacerbate dementia‐type symptoms such as memory loss and executive dysfunction. Recent work in our lab demonstrated, for the first time, a link between stroke, AD‐related pathology, and WM inflammation. A unilateral lacunar stroke induction in a comorbid rat model of AD and stroke resulted in microglial activation within the WM tracts and subsequent impairment in behavioural flexibility, an important component of executive function. As such, the aim of the current study was to evaluate the effect of microglia targeting on WM pathology, executive function, learning, and memory in the co‐morbid rat model of AD (TgAPP21) and stroke. Minocycline, a tetracycline‐class antibiotic and an anti‐inflammatory drug, has been shown to decrease apoptosis, inflammation, and microglial activation following cerebrovascular injury. To study the behavioural outcomes of minocycline treatment, TgAPP21 rats received an endothelin‐1‐induced subcortical stroke at the age of 8 months. Following stroke, animals received intraperitoneal injections of minocycline or saline twice daily for four days to supress microglial activation. Cognitive behavioural flexibility post‐stroke was analyzed using set‐shifting operant conditioning test, while spatial learning and memory were assessed using Morris water maze. Immunohistochemistry was performed to evaluate the extent of microglial activation by detection of OX‐6 positive microglia in corpus callosum, internal capsule, and hippocampus. Minocycline treatment significantly decreased the number of errors committed by TgAPP21 rats on the visual cue component of the set‐shifting test, suggesting improved learning of the original visual cue task. However, minocycline also impaired animals’ ability to undergo an extra‐dimensional strategy shift from the original visual cue to a new spatial cue task, suggesting impaired behavioural flexibility. Further, minocycline treatment showed no significant effect on learning and memory of the Morris water maze task in TgAPP21 rats. Collectively, the data indicate that minocycline has distinct effects on the learning component of set‐shifting and Morris water maze tests, though further histological evaluation of OX‐6 positive microglia within WM tracts and hippocampus will contextualize current findings. Support or Funding Information Natural Sciences and Engineering Research Council (NSERC), Canadian Institutes of Health Research (CIHR), Canadian Foundation for Innovation (CFI), Canadian Consortium for Neurodegeneration and Aging (CCNA)
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".